Ferric carboxymaltose improves cardiac function in patients with HFrEF and iron deficiency

The effect of intravenous ferric-carboxymaltose on cardiac reverse remodeling following cardiac resynchronization therapy - The IRON CRT trial.

Presented at ESC Heart Failure 2021 by Pieter Martens, MD, PhD (Genk, Belgium)

Introduction and methods

Iron deficiency is highly prevalent in patients with HFrEF. Iron deficiency is associated with progressive cardiac remodeling, diminished cardiac/cardiomyocyte contractility and reduced cardiac energy reserve. While it is know that ferric carboxymaltose (FCM) improves functional status and reduces risk for HF admission in patients with HF, the cardiac effects of FCM treatment are relatively unknown.

The IRON-CRT trial was a randomized, double blind controlled trial that investigated whether FCM induces reverse remodeling in patients with symptomatic HFrEF with persistently reduced LVEF <45%, iron deficiency and a CRT device. An additional goal of IRON-CRT was to determine if FCM improves the force frequency relationship. The study specifically enrolled patients with a CRT device to perform a validated force frequency pacing protocol. Patients were randomized to receive either FCM (n=37) or standard of care (SOC, n=38). The primary endpoint was change in LVEF from baseline to 3 months follow-up (measured by 3D echocardiography). Secondary endpoints included change in LVESV and LVEDV from baseline to 3 months follow-up (also measured by 3D echocardiography), and change in force frequency relationship (measured noninvasively by the cardiac contractility index [SBP/LVESVi] at 70-90-110 BPM biventricular pacing). Tertairy endpoints included change in peak VO2 and VE/VCO2 ratio, change in KCCQ, and change in NTproBNP.

Main results

• Change in LVEF from baseline to 3 months follow-up was significantly higher in the FCM group, compared to the SOC group (FCM: +4.22%, 95%CI +3.05 to +5.38%; SOC: -0.23%, 95%CI -1.44% to +0.97%; difference between treatment groups P<0.001).
• The improvement in LVEF in the FCM appeared to be driven by a significant reduction in LVESV. Change in LVESV from baseline to 3 months follow-up was significantly more pronounced in the FCM group, compared to the SOC group (FCM: -9.72 ml, 95%CI -13.5 to -5.93 ml; SOC: -1.83 ml, 95%CI -5.7% to +2.1 ml; group difference P=0.001).
• Change in LVEDV did not differ significantly between the FCM and SOC groups (FCM: -2.5 ml, 95%CI -5.3 to +0.3 ml; SOC:-1.9 ml, 95%CI -4.7 to +1.0 ml; group difference P=0.748).
• At 3 months follow-up, a positive force frequency relationship was observed in the FCM group, while a negative force frequency relationship was seen in the SOC group. Patients in the FCM group had a significant improvement in the cardiac contractility index-slope, compared to patients in the SOC group. In patients randomized to FCM, the cardiac contractility index-slope improved from a negative slope at baseline to a positive slope at 3 months follow-up (difference baseline vs. follow-up P<0.001). This change was not seen in the SOC group (difference baseline vs. follow-up P=0.714).
• Significant improvements in peak VO2 and KCCQ were observed in the FCM group compared to the SOC group. There were no significant differences in VE/VCO2 and NTproBNP between groups.
• Subgroup analysis in three predefined subgroups (LVEF<35% vs. ≥35%, TSAT ≥20% vs. <20%, and Hb <12g/dl vs. ≥12 g/dl) showed a consistent effect of FCM on the primary endpoint of change in LVEF from baseline to 3 months follow-up in all subgroups. Interaction analysis showed that patients with TSAT ≥20% had less improvement in LVEF than patients with TSAT <20% (P-value for interaction = 0.0362).
• Treatment with FCM was not associated with higher risk for adverse events in comparison to SOC.

Conclusions

Treatment with FCM in HFrEF patients with iron deficiency and persistently reduced LVEF (<45%) despite optimal medical therapy and CRT resulted in cardiac reverse remodeling (measured by an improvement in LVEF and reduction in LVESV) over a follow-up of 3 months. Additionally, treatment with FCM transformed a negative force frequency relationship at baseline to a positive force frequency relationship at 3 months follow-up. FCM also improved the functional status of patients (KCCQ) and maximal exercise capacity (PeakVO2).

-Our reporting is based on the information provided at the ESC Heart Failure 2021 congress-

The results of this study were simultaneously published in Eur Heart J.